PROJECT SUMMARY/ABSTRACT The proposed project assesses the mechanistic basis for the pathogenesis of disease driven by Leishmania, a protozoal parasite that causes cutaneous lesions. Following infection, lesion severity is often increased by an exaggerated inflammatory response. As a result, the inflammatory response can maintain the disease even after the parasite infection has been controlled. Given vascular remodeling contributes to the magnitude of many inflammatory conditions, it is hypothesized that the manipulation of factors promoting vascular remodeling would provide a novel approach to limit immunopathology in leishmaniasis. My recently published findings demonstrate for the first time that murine Leishmania major infection leads to dramatic changes in vessel morphology, number and permeability. At the peak of infection, VEGF-A and VEGFR-2 expression are upregulated and VEGFR-2 blockade to mice with established lesions led to decreased pathology. These data led to the central hypothesis that the VEGF-A/VEGFR-2 signaling pathway promotes vascular remodeling that drives immunopathology in Leishmania infection and that inhibition of this pathway will limit disease severity. In Aim 1, the cellular and molecular mediators driving VEGF-A production will be identified. Preliminary results show for the first time that parasites directly induce VEGF-A production in a HIF-dependent manner, so the in vivo role of VEGF-A and HIF will be examined using genetic and chemical manipulation. In contrast, VEGFR-2 blockade from the onset of infection increases lesion sizes without altering parasite numbers. Therefore, Aim 2 will determine the cell types responding to VEGF-A and examine the effects of modulating HIF-mediated VEGF-A/VEGFR-2 signaling at different time points following infection. The proposed studies will define the multiple roles of VEGF-A during leishmaniasis, thereby providing mechanisms by which VEGF-A/VEGFR-2 signaling contributes to immunopathology. The data generated will have profound implications for immunotherapeutic strategies for leishmaniasis as well as other inflammatory diseases. Altogether, the proposed research plan along with my training, institutional resources, and a team of supporting colleagues, will provide me with the intellectual and technical skillset to produce a scientific body of work that will redefine the paradigm of disease pathogenesis associated with Leishmania infection.